Clinical course predicts long-term outcomes in bipolar disorder.

BACKGROUND: The long-term outcomes of bipolar disorder range from lasting remission to chronic course or frequent recurrences requiring admissions. The distinction between bipolar I and II disorders has limited utility in outcome prediction. It is unclear to what extent the clinical course of bipolar disorder predicts long-term outcomes. METHODS: A representative sample of 191 individuals diagnosed with bipolar I or II disorder was recruited and followed for up to 5 years using a life-chart method. We previously described the clinical course over the first 18 months with dimensional course characteristics and latent classes. Now we test if these course characteristics predict long-term outcomes, including time ill (time with any mood symptoms) and hospital admissions over a second non-overlapping follow-up period in 111 individuals with available data from both 18 months and 5 years follow-ups. RESULTS: Dimensional course characteristics from the first 18 months prospectively predicted outcomes over the following 3.5 years. The proportion of time depressed, the severity of depressive symptoms and the proportion of time manic predicted more time ill. The proportion of time manic, the severity of manic symptoms and depression-to-mania switching predicted a greater likelihood of hospital admissions. All predictions remained significant after controlling for age, sex and bipolar I v. II disorder. CONCLUSIONS: Differential associations with long-term outcomes suggest that course characteristics may facilitate care planning with greater predictive validity than established types of bipolar disorders. A clinical course dominated by depressive symptoms predicts a greater proportion of time ill. A clinical course characterized by manic episodes predicts hospital admissions.

Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors.

Recent experimental animal studies have shown that fetal exposure to serotonin reuptake inhibitors (SRIs) affects brain development. Modern recording methods and advanced computational analyses of scalp electroencephalography (EEG) have opened a possibility to study if comparable changes are also observed in the human neonatal brain. We recruited mothers using SRI during pregnancy (n = 22) and controls (n = 62). Mood and anxiety of mothers, newborn neurology, and newborn cortical function (EEG) were assessed. The EEG parameters were compared between newborns exposed to drugs versus controls, followed by comparisons of newborn EEG features with maternal psychiatric assessments. Neurological assessment showed subtle abnormalities in the SRI-exposed newborns. The computational EEG analyses disclosed a reduced interhemispheric connectivity, lower cross-frequency integration, as well as reduced frontal activity at low-frequency oscillations. These effects were not related to maternal depression or anxiety. Our results suggest that antenatal serotonergic treatment might change newborn brain function in a manner compatible with the recent experimental studies. The present EEG findings suggest links at the level of neuronal activity between human studies and animal experiments. These links will also enable bidirectional translation in future studies on the neuronal mechanisms and long-term neurodevelopmental effects of early SRI exposure.

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial.

BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

Incidence and predictors of suicide attempts in bipolar I and II disorders: A 5-year follow-up study.

OBJECTIVES: Few long-term studies on bipolar disorder (BD) have investigated the incidence and risk factors of suicide attempts (SAs) specifically related to illness phases. We examined the incidence of SAs during different phases of BD in a long-term prospective cohort of bipolar I (BD-I) and bipolar II (BD-II) patients, and risk factors specifically for SAs during major depressive episodes (MDEs). METHODS: In the Jorvi Bipolar Study (JoBS), 191 BD-I and BD-II patients were followed using life-chart methodology. Prospective information on SAs of 177 patients (92.7%) during different illness phases was available up to 5 years. The incidence of SAs and their predictors were investigated using logistic and Poisson regression models. Analyses of risk factors for SAs occurring during MDEs were conducted using two-level random-intercept logistic regression models. RESULTS: During the 5 years of follow-up, 90 SAs per 718 patient-years occurred. The incidence was highest, over 120-fold higher than in euthymia, during mixed states (765/1000 person-years; 95% confidence interval [CI] 461-1269 person-years), and also very high in MDEs, almost 60-fold higher than in euthymia (354/1000 person-years; 95% CI 277-451 person-years). For risk of SAs during MDEs, the duration of MDEs, severity of depression, and cluster C personality disorders were significant predictors. CONCLUSIONS: We confirmed in this long-term study that the highest incidences of SAs occur in mixed and major depressive illness phases. The variations in incidence rates between euthymia and illness phases were remarkably large, suggesting that the question "when" rather than "who" may be more relevant for suicide risk in BD. However, risk during MDEs is likely also influenced by personality factors.

Diabetes and Schizophrenia.

People with schizophrenia have 2- to 5-fold higher risk of type 2 diabetes than the general population. The traditional risk factors for type 2 diabetes, especially obesity, poor diet, and sedentary lifestyle, are common in people with schizophrenia already early in the course of illness. People with schizophrenia also often have low socioeconomic status and income, which affects their possibilities to make healthy lifestyle choices. Antipsychotic medications increase the risk of type 2 diabetes both directly by affecting insulin sensitivity and indirectly by causing weight gain. Lifestyle modification interventions for prevention of diabetes should be an integral part of treatment of patients with schizophrenia. In the treatment of type 2 diabetes in patients with schizophrenia, communication and collaboration between medical care and psychiatric treatment providers are essential.

Predictors of long-term work disability among patients with type I and II bipolar disorder: a prospective 18-month follow-up study.

OBJECTIVES: Bipolar disorder (BD) is one of the leading causes of disability worldwide. However, vocational ability and predictors of long-term work disability have rarely been studied among patients with BD. We investigated clinical predictors of work disability among patients with BD in psychiatric care. METHODS: The Jorvi Bipolar Study (JoBS) is a naturalistic prospective cohort study (N = 191) representing adult (18-59 years) psychiatric inpatients and outpatients with DSM-IV bipolar I disorder (BD-I) and bipolar II disorder (BD-II) in three Finnish cities. Within the JoBS, we investigated the prevalence of disability pensions at baseline, and predictors for being granted a disability pension during an 18-month follow-up of the 151 patients in the labor force at baseline. Cox models were used to determine predictors for onset of disability pension. RESULTS: At baseline, 21% (40/191) of the patients already had a disability pension. During the follow-up, a further 38 patients (25% of the 151 followed) were granted a new disability pension. The predictors included older age, male gender, depressive index episode, higher number of psychiatric hospitalizations, generalized anxiety disorder, avoidant personality disorder, and depressive burden during follow-up. However, the predictors differed depending on bipolar subtype, age, and gender. CONCLUSIONS: BD-I and BD-II are associated with a major risk of long-term work disability, the proportion of patients with a disability pension rising to 41% in the medium-term follow-up of the Finnish cohort investigated in the present study. Severe clinical course, depression, comorbidities, age, and gender are likely to be the main predictors but predictors may vary depending on the subgroup.

Five-year outcome of bipolar I and II disorders: findings of the Jorvi Bipolar Study.

OBJECTIVES: The long-term outcome of bipolar disorder (BD) has been extensively investigated. However, previous studies may be biased towards hospitalized patients with bipolar I disorder (BD-I), and generalizability to the current treatment era remains uncertain. In this naturalistic study, we followed a secondary-care cohort of patients with BD. METHODS: In the Jorvi Bipolar Study, 191 patients with BD-I and bipolar II disorder (BD-II) were followed using a life-chart method. Interviews were conducted at six months, 18 months, and five years. Time to full remission, time to first recurrence, total time ill, their predictors, and BD-I versus BD-II differences were investigated among the 151 patients remaining in follow-up. RESULTS: Nearly all subjects recovered from the index episode, but almost all (90%) had a recurrence, and most had multiple recurrences. The patients spent about one-third of their time in illness episodes and 15% of their time with subthreshold symptoms; half of the time they were euthymic. After controlling for confounders, no difference in time spent in depressive states between patients with BD-I and BD-II persisted. Among patients with a depressive index phase, cluster C personality disorders [hazard ratio (HR) = 0.452, p = 0.040] and higher 17-item Hamilton Depression Scale score (HR = 0.951, p = 0.022) predicted longer time to remission, whereas lifetime psychotic symptoms (HR = 2.162, p = 0.016) predicted shorter time to first recurrence. CONCLUSIONS: Among patients with BD, chronicity as uninterrupted persistence of illness was rare, but multiple recurrences were the norm. Patients with BD spent only half of their time euthymic. Patients with BD-I and BD-II may differ little in proneness to depressive states. Severity of depression, cluster C personality disorders, and psychotic symptoms predicted outcome.

[Recognition of mood disorders]. / Mielialahäiriön monet kasvot--tunnistanko?

A mood disorder involves lowering or elevation or mood and usually also somatic symptoms associated with anxiety, substance abuse problems or a personality disorder. In addition to diagnoses, the stage and degree of severity of the disorder and the patients' own motivation influence the treatability of the patients. The expectations and hopes of the patients are associated with their life and medical history, social situations and increasingly heterogenous cultural backgrounds. A good and continuous therapeutic relationship can contribute to the treatment motivation and result.

Differences in incidence of suicide attempts between bipolar I and II disorders and major depressive disorder.

OBJECTIVES: Whether risk of suicide attempts (SAs) differs between patients with bipolar disorder (BD) and patients with major depressive disorder (MDD) is unclear. We investigated whether cumulative risk differences are due to dissimilarities in time spent in high-risk states, incidence per unit time in high-risk states, or both. METHODS: Incidence rates for SAs during various illness phases, based on prospective life charts, were compared between patients from the Jorvi Bipolar Study (n = 176; 18 months) and the Vantaa Depression Study (n = 249; five years). Risk factors and their interactions with diagnosis were investigated with Cox proportional hazards models. RESULTS: By 18 months, 19.9% of patients with BD versus 9.5% of patients with MDD had attempted suicide. However, patients with BD spent 4.6% of the time in mixed episodes, and more time in major depressive episodes (MDEs) (35% versus 21%, respectively) and in subthreshold depression (39% versus 31%, respectively) than those with MDD. Compared with full remission, the combined incidence rates of SAs were 5-, 25-, and 65-fold in subthreshold depression, MDEs, and BD mixed states, respectively. Between cohorts, incidence of attempts was not different during comparable symptom states. In Cox models, hazard was elevated during MDEs and subthreshold depression, and among patients with preceding SAs, female patients, those with poor social support, and those aged < 40 years, but was unrelated to BD diagnosis. CONCLUSIONS: The observed higher cumulative incidence of SAs among patients with BD than among those with MDD is mostly due to patients with BD spending more time in high-risk illness phases, not to differences in incidence during these phases, or to bipolarity itself. BD mixed phases contribute to differences involving very high incidence, but short duration. Diminishing the time spent in high-risk phases is crucial for prevention.

[Psychiatric legislation for the emergency physician]. / Psykiatrinen lainsäädäntö päivystäjälle.

A psychiatric examination in an emergency care situation often involves taking an attitude towards the patient's right to preserve her/his freedom and integrity. In the name of human rights it has been considered important to carefully control the reasons and courses of action that are used to restrict the constitutional rights of a human being. This will inevitably necessitate the adherence to certain formal courses of action. The goal shall be an attempt to patient-centered thinking and encountering the patient as a human being. Treatment possibilities in outpatient care should be good enough to be more frequently utilized instead of involuntary care.

[A young person in psychiatric emergency service]. / Nuori psykiatrisessa päivystyksessä.

In a psychiatric emergency call situation an under-age person is entitled to make decisions concerning her/himself and her/his treatment, and the physician shall act for the young person's best. When necessary, child protection should be informed and in suspected sexual offence, also the police. The assessment of the need for psychiatric treatment must be based on patient history evaluated under undisturbed conditions. The young person and the raisers are interviewed together and separately. The participation of parents in the psychiatric therapy of a young person is the principal rule. Outpatient care is the primary method. Psychotropic medication for a young person in an emergency call situation is started only in exceptional cases.

Neuroticism mediates the effect of P2RX7 on outcomes of mood disorders.

BACKGROUND: We previously reported an association between P2RX7 variant rs208294, diagnosis, and the longitudinal course of mood disorders. Here, we test whether the personality trait neuroticism mediates the effect of P2RX7 on the course of mood disorders. METHODS: Patients with DSM-IV mood disorder (256 with major depressive disorder and 168 with bipolar disorder [BD]) were diagnosed with semistructured interviews, genotyped, and followed up for a median of 60 (range 6-83) months. The primary outcome was the prospectively assessed proportion of time spent in any DSM-IV mood episode (time ill). Three types of genetic effect were tested in structural equations models: Model 1: genes directly affect outcome independent of neuroticism, Model 2: neuroticism mediates the effect of genes on outcome, and Model 3: neuroticism and the genetic variant interact in their effect on outcome. RESULTS: Neuroticism mediated the P2RX7 genetic effect on outcome. The T allele of rs208294 was associated with higher neuroticism, which in turn predicted a higher proportion of time spent in mood episodes (the bootstrap-based test of indirect effect, P = .02). There was no significant interaction between neuroticism and the genotype. CONCLUSION: Neuroticism is likely to lie on the causal pathway between the rs208294 T variant and the adverse long-term course of major depressive and BDs.

Concomitants of family histories of mood disorders and alcoholism in a clinical cohort of patients with bipolar I and II disorder.

We diagnosed 191 secondary-care outpatients and inpatients with DSM-IV BD I or II. Sociodemographic and clinical characteristics, including axis I and II comorbidity, neuroticism, and prospective life-chart were evaluated at intake and at 6 and 18 months. The family history (FH) of mood disorders, alcoholism, or any major psychiatric disorders among first-degree relatives was investigated in a semistructured interview. Most (74%) patients had some positive FH; 55% of mood disorder, 36% of alcoholism. Positive FH was associated with psychiatric comorbidity and depressive course in the proband. Based on a multinomial logistic regression model, patients with an FH of mood disorder and alcoholism had an odds ratio of 4.8 (p = 0.001) for having an anxiety disorder. Overall, the first-degree relatives of patients with BD have multiple types of mental disorders, which correlate with bipolar patients' course of illness and psychiatric comorbidity. The strongest associations are between FH of mood disorders and presence of comorbid anxiety disorders.

P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts.

We investigated the effect of nine candidate genes on risk for mood disorders, hypothesizing that predisposing gene variants not only elevate the risk for mood disorders but also result in clinically significant differences in the clinical course of mood disorders. We genotyped 178 DSM-IV bipolar I and II and 272 major depressive disorder patients from three independent clinical cohorts carefully diagnosed with semistructured interviews and prospectively followed up with life charts for a median of 60 (range 6-83) months. Healthy control subjects (n = 1322) were obtained from the population-based national Health 2000 Study. We analyzed 62 genotyped variants within the selected genes (BDNF, NTRK2, SLC6A4, TPH2, P2RX7, DAOA, COMT, DISC1, and MAOA) against the presence of mood disorder, and in post-hoc analyses, specifically against bipolar disorder or major depressive disorder. Estimates for time ill were based on life charts. The P2RX7 gene variants rs208294 and rs2230912 significantly elevated the risk for a familial mood disorder (OR = 1.35, P = 0.0013, permuted P = 0.06, and OR = 1.44, P = 0.0031, permuted P = 0.17, respectively). The results were consistent in all three cohorts. The same risk alleles predicted more time ill in all cohorts (OR 1.3, 95% CI 1.1-1.6, P = 0.0069 and OR 1.7, 95% CI 1.3-2.3, P = 0.0002 with rs208294 and rs2230912, respectively), so that homozygous carriers spent 12 and 24% more time ill. P2RX7 and its risk alleles predisposed to mood disorders consistently in three independent clinical cohorts. The same risk alleles resulted in clinically significant differences in outcome of patients with major depressive and bipolar disorder.

[Maintenance therapy in bipolar affective disorder]. / Ylläpitohoito kaksisuuntaisessa mielialahäiriössä.

In bipolar affective disorder, the patients exhibit life-long susceptibility to periodic episodes of depression, mania, hypomania, including mixed phases. Maintenance therapy aims to prevent new episodes of affective disorder and associated self-destructive behavior, to prevent milder symptoms occurring between the actual episodes and to maintain functional capacity. Maintenance therapy is always initiated upon the diagnosis of bipolar affective disorder. In a type II disorder with mild symptoms, gradual termination of maintenance therapy can be considered while monitoring the status of the patient. The drug is chosen on the basis of individual benefit/risk ratio.

A prospective latent analyses study of psychiatric comorbidity of DSM-IV bipolar I and II disorders.

OBJECTIVE: To test two hypotheses of psychiatric comorbidity in bipolar disorder (BD): (i) comorbid disorders are independent of BD course, or (ii) comorbid disorders associate with mood. METHODS: In the Jorvi Bipolar Study (JoBS), 191 secondary-care outpatients and inpatients with DSM-IV bipolar I disorder (BD-I) or bipolar II disorder (BD-II) were evaluated with the Structured Clinical Interview for DSM-IV Disorders, with psychotic screen, plus symptom scales, at intake and at 6 and 18 months. Three evaluations of comorbidity were available for 144 subjects (65 BD-I, 79 BD-II; 76.6% of 188 living patients). Structural equation modeling (SEM) was used to examine correlations between mood symptoms and comorbidity. A latent change model (LCM) was used to examine intraindividual changes across time in depressive and anxiety symptoms. Current mood was modeled in terms of current illness phase, Beck Depression Inventory (BDI), Young Mania Rating Scale, and Hamilton Depression Rating Scale; comorbidity in terms of categorical DSM-IV anxiety disorder diagnosis, Beck Anxiety Inventory (BAI) score, and DSM-IV-based scales of substance use and eating disorders. RESULTS: In the SEM, depression and anxiety exhibited strong cross-sectional and autoregressive correlation; high levels of depression were associated with high concurrent anxiety, both persisting over time. Substance use disorders covaried with manic symptoms (r = 0.16-0.20, p < 0.05), and eating disorders with depressive symptoms (r = 0.15-0.32, p < 0.05). In the LCM, longitudinal intraindividual improvements in BDI were associated with similar BAI improvement (r = 0.42, p < 0.001). CONCLUSIONS: Depression and anxiety covary strongly cross-sectionally and longitudinally in BD. Substance use disorders are moderately associated with manic symptoms, and eating disorders with depressive mood.

The effect of atorvastatin on cognition and mood in bipolar disorder and unipolar depression patients: A secondary analysis of a randomized controlled trial.

OBJECTIVES: Statins have recently been linked to having effects on cognition and mood in mood disorders, though results are mixed. In this paper, we use data from a recent randomized controlled trial (RCT) to examine the effect of statins on cognition and mood in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). METHODS: This is a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial (n = 60) originally designed to examine the effect of atorvastatin (n = 27) versus placebo (n = 33) for lithium-induced diabetes insipidus in BD and MDD patients who were using lithium. For this analysis, the primary outcome was global cognition Z-score at 12-weeks adjusted for baseline. The secondary cognition outcomes were (1) Screen for Cognitive Impairment in Psychiatry (SCIP), and (2) executive function Z-score. The primary mood outcome (secondary outcome of this analysis) was depression relapse during 12-week follow-up (Mongomery Asberg Depression Rating Scale (MADRS) ≥10). The secondary mood outcomes were (1) relapse rate into a manic episode, and (2) relapse rate into any mood episode. RESULTS: After 12 weeks follow-up, atorvastatin and placebo groups did not differ in terms of global cognition Z-score (ß = -0.009287 (-0.1698,0.1512), p-value = 0.91). Similarly, composite Z-scores for SCIP and executive functions did not differ significantly. Depression relapse during 12-week follow-up was not significantly different between the groups (χ2 (1) = 0.148, p-value = 0.70). Similarly, there was no difference between groups regarding relapse into mania. CONCLUSION: In BD and MDD patients with lithium-induced nephrogenic diabetes insipidus randomized to atorvastatin or placebo, we found no significant differences in cognition and mood outcomes at 12-week follow-up.

Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis.

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.

Predominant polarity in bipolar I and II disorders: A five-year follow-up study.

BACKGROUND: Patients with bipolar disorder (BD) differ in their relative predominance of types of episodes, yielding predominant polarity, which has important treatment implications. However, few prospective studies of predominant polarity exist. METHODS: In the Jorvi Bipolar Study (JoBS), a regionally representative cohort of 191 BD I and BD II in- and outpatients was followed for five years using life-chart methodology. Differences between depressive (DP), manic (MP), and no predominant polarity (NP) groups were examined regarding time ill, incidence of suicide attempts, and comorbidity. RESULTS: At baseline, 16% of patients had MP, 36% DP, and 48% NP. During the follow-up the MP group spent significantly more time euthymic, less time in major depressive episodes, and more time in manic states than the DP and NP groups. The MP group had significantly lower incidence of suicide attempts than the DP and NP group, lower prevalence of comorbid anxiety disorders but more psychotic symptoms lifetime and more often (hypo)manic first phase of the illness than the DP group. Classification of predominant polarity was influenced by the timeframe used. LIMITATIONS: The retrospective counting of former phases is vulnerable to recall bias. Assignment of dominant polarity may necessitate a sufficient number of illness phases. CONCLUSIONS: Predominant polarity has predictive value in predicting group differences in course of illness, but individual patients' classification may change over time. Patients with manic polarity may represent a more distinct subgroup than the two others regarding illness course, suicide attempts, and psychiatric comorbidity.